Reversing the New Anticoagulants - UCSF CME11/6/2013 2 Roadmap for today • Characteristics of novel anticoagulants • Approach to the bleeding patient • Specific reversal agents

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Reversing the New AnticoagulantsSusan C. Lambe, MDAssistant Clinical ProfessorDepartment of Emergency MedicineUniversity of California, San Francisco

Disclosure

Roadmap for today

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Roadmap for today• Characteristics of novel anticoagulants• Approach to the bleeding patient• Specific reversal agents• UCSF guidelines

Scope of Problem• Prevalence atrial fibrillation

• 3.03 million in 2005 • 7.56 million by 2050

• VTE = 900K/yr in US• 1-2% of adults take warfarin

Warfarin1920s – Outbreak hemorrhagic disease in cattle in

northern US and Canada1933 – Isolated by Karl Link1948 – Rodenticde1954 – Approved in humans

WARF-arin

Wisconsin Alumni Research FoundationCoumarin, plant molecule in sweet clover

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Warfarin Disadvantages• Bridging• Drug and food interactions• Long half-life• Close monitoring required

Why New Anticoagulants?• Rapid onset/shorter half-life• Fewer drug and no food interactions• No lab monitoring• Equivalent to warfarin

• Prevention of stroke, VTE• Bleeding rates

New Anticoagulant Disadvantages

• Limited experience treating bleeding

• No proven reversal agent• No monitoring

What’s in a name?

• Direct Thrombin Inhibitors (DTIs)• Novel Oral Anticoagulants (NOACS)• Target Specific Oral Anticoagulants (TSOACS)

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Roadmap for today• Characteristics of novel anticoagulants• Approach to the bleeding patient• Specific reversal agents• UCSF Guidelines

New Anticoagulants

• Dabigatran (Pradaxa®)• Rivaroxaban (Xarelto®)• Apixaban (Eliquis®)

New Anticoagulants• Dabigatran (Pradaxa®)• Rivaroxaban (Xarelto®)• Apixaban (Eliquis®)

Dabigatran Indications• FDA approved

• Stroke prevention in non-valvular afib• Under FDA review

• VTE prophylaxis in hip or knee replacement• Approved in Europe/Canada

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Dabigatran Dose

• Stroke prevention• 150 mg, po bid• Renal insufficiency 75 mg, po bid

• DVT prophylaxis• 220 mg, po qd

Dabigatran Mechanism• Direct Thrombin (Factor IIa) inhibitor• Blocks conversion of fibrinogen to fibrin

Dabigatran Pharmacology

• Dabigatran etexilate = inactive pro-drug• Rapidly absorbed• Active form binds active site of thrombin• Inhibits free and clot-bound thrombin

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Dabigatran Pharmacokinetics• Predictable• Rapid onset• Peak plasma level at 2 hours• Half-life 14-17 hours

Dabigatran Pharmacokinetics

• No food interactions, few drug interactions• Fixed dosing can be used• No need for routine monitoring or dose adjustment

Dabigatran Metabolism• 85% excreted via the kidneys• Use caution with renal dysfunction• Low protein binding

• Eliminated by hemodialysis

Dabigatran Metabolism• NOT metabolized by p450 system• Substrate of efflux transporter P-glycoprotein

• Inducers (e.g., rifampin) reduce effect• Inhibitors (e.g., verapamil) increase effect

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Dabigatran Metabolism• Decreased effect with P-gP inducers

• Rifampin• Increased effect with P-gP inhibitors

• Dronedarone• Ketoconazole, Itraconazole• Verapamil• Amiodarone• Quinidine• Clarithromycin

New Anticoagulants• Dabigatran (Pradaxa®)• Rivaroxaban (Xarelto®)• Apixaban (Eliquis®)

FACTOR Xa INHIBITORSRivaroxaban

(Xarelto®)Apixaban (Eliquis®)

Indications• Rivaroxaban/Apixaban

• Stroke prevention in non-valvular atrial fib• Rivaroxaban only

• VTE prophylaxis post-joint replacement• DVT/PE prophylaxis and treatment

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Rivaroxaban and Apixaban DoseNon-valvular afib• Rivaroxaban, 20 mg po qd• Apixaban, 5 mg po qdDVT/PE• Rivaroxaban, 15 mg po qdDVT prophylaxis• Rivaroxaban,10 mg po qd

Rivaroxaban and Apixaban Mechanism

Selective, direct, factor Xa inhibitors

Rivaroxaban and Apixaban Pharmacology

• Highly protein bound• Not easily dialyzed• Few drug interactions

Rivaroxaban and Apixaban Pharmacokinetics

• Similar to dabigatran• Predictable

• Not affected by age, sex, body weight• Fixed dose

• Peak at 2 – 3h• Half life 7-14h

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MetabolismRivaroxaban

• Excretion• 2/3rd renal• 1/3rd liver

• Dose adjusted for reduced CrCl

Apixaban• Excretion

• 2/3rd liver, biliary• 1/3rd renal

Coagulation Assays• Not routinely necessary• Indications

• Major bleeding• Overdose• Emergent surgery

Coagulation AssaysDabigatran• Peak/trough 20-300 ng/ml• aPTT

• Prolonged at >50 ng/ml• Normal at 25 ng/ml

• Thrombin time• Prolonged at 3 ng/ml• Normal at 1 ng/ml

Coagulation AssaysDabigatran• aPTT not useful• Thrombin time

• If normal, dabigatran not present

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Coagulation AssaysRivaroxaban/Apixaban• Peak/trough 25-400 ng/ml• aPTT

• Prolonged at 120 ng/ml• Normal at 60 ng/ml

Coagulation AssaysRivaroxaban/Apixaban• Anti-factor Xa assay

• No assay for rivaroxaban available• Ask for assay calibrated for enoxaparin• Estimate of rivaroxaban/apixaban activity


Approach to Bleeding• Discontinue anticoagulant• Compress• Fluid replacement, transfusion

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Approach to BleedingConsider emergent reversal• Intracranial• Pericardial• Intraspinal• Hemorrhagic shock• Drug overdose• Emergency surgery


Reversal AgentsNO ROLE FOR VITAMIN K IN REVERSAL

OF NEW ORAL ANTICOAGULANTS

Reversal: Options• Hemodialysis (dabigatran only)• Prothombin complex concentrate (PCC)• Recombinant Factor VIIa (rFVIIa)• aPCC (FEIBA®)

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Reversal: HemodialysisFor reversing dabigatranEvidence

• 6 healthy volunteers w ESRD• 62% removed after 2 hours• 68% removed after 4 hours

Rivaroxaban/apixaban too highly protein-bound for HD

Stangier, 2010

Reversal: PCCTwo preparations

• Kcentra® 4-factor PCC (II, VII, IX, X)• Bebulin® 3-factor PCC (II, IX, X)

Reversal: Specific AgentsHuman studiesAnimal studiesSpecific Antidotes

Reversal: Specific AgentsHuman studiesAnimal studiesSpecific Antidotes

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Reversal: Specific AgentsHuman studies• 5 studies, 2011-2013• Healthy volunteers • Anticoagulants: dabigatran, rivaroxaban, apixaban• Reversal agents

• PCC• aPCC• rFVIIa

• Outcome: clotting assays

Reversal: Human Studies

Erenberg, 2011• Study design

• N=12 subjects• Dabigatran or rivaroxaban po x 2.5 d• Treated with PCC bolus iv• Measured PT and ETP over 24 hours


Erenberg, 2011• Findings

• PCC reversed PT, ETP in rivaroxaban treated patients

• PCC did not reverse dabigatran

Reversal: Human StudiesMarlu, 2012• Study design

• N=10 men• Dabigatran or rivaroxaban po x 1• Collected blood samples• Treated blood (PCC, rFVIIa, aPCC)

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Marlu, 2012• Findings

• Dabigatran• rFVIIa most effective

• Rivaroxaban• PCC most effective

Reversal: Human StudiesKhoo, 2013• Dabigatran+aPCC• Study design

• N=8 subjects on dabigatran• Blood treated with aPCC

Reversal: Human StudiesKhoo, 2013

• Findings• aPCC reversed dabigatran

Reversal: Human StudiesDinklaar, 2013• Rivaroxaban+PCC• Study Design

• N=9 subjects• PCC added to rivaroxaban-treated samples• Coagulation assays performed

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Reversal: Human StudiesDinklaar, 2013• Rivaroxaban + PCC

• Findings – mixed results• PCC

• Normalized thrombin generation• Did not normalize PT

• Dose of PCC required depended on type of assay

Reversal: Human StudiesKorber, 2013Rivaroxaban + PCC/rFVIIa• Study design

• N=10 subjects• Blood samples treated with rivaroxaban• Added PCC and rVIIa• Performed clotting assays

Reversal: Human StudiesKorber, 2013Rivaroxaban + PCC/rVIIa• Findings

• PCC had no effect on clotting tests• rVIIa reversed PT and clotting factor time

prolongation

Human Studies: SummaryDabigatran• Reversed with aPCC in 2/2 studiesRivaroxaban• Reversed with PCC in 3/4 studies

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Human studies: Limitations• Variable designs• Healthy volunteers• Reversal agents added to blood samples• Clotting tests proxy for bleeding

Reversal: Specific AgentsHuman studiesAnimal studiesSpecific antidotes

Reversal: Animal studies• 6 studies, 2008-2013• Anticoagulants:

• Dabigatran• Rivaroxaban• Apixaban

• Reversal agents• PCC• rFVIIa• aPCC (FEIBA®)• Fibrinogen• FFP

• Outcomes• Clotting assays• Bleeding

Reversal: Animal StudiesVan Ryn, 2008• Study Design

• Rats infused w high dose dabigatran x 20 min• Reversed with rFVIIa and aPCC (FEIBA®) given iv• Bleeding measured 5 min after tail incision

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Reversal: Animal StudiesVan Ryn, 2008• Findings

• Both agents reduced bleeding time• Neither agent reduced blood loss

Reversal: Animal StudiesZhou, 2011• Study Design

• Mice were treated with dabigatran po• ICH induced

• Reversed with intravenous• PCC• Murine FFP• rFVIIa

Reversal: Animal StudiesZhou, 2011• Findings

• N=96 mice• PCC prevented hematoma expansion• Murine FFP worked only with high dose dabigatran• rFVIIa did not prevent hematoma expansion

Reversal: Animal StudiesGodier, 2012• Study Design (n=83 rabbits)

• T=0 min, rivaroxaban iv • T=1 min, procoagulant iv (PCC, rFVIIa)• Hepatosplenic bleeding induced• T=15 min, total blood loss recorded

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Reversal: Animal StudiesGodier, 2012• Findings

• Neither rFVIIa nor PCC reduced total blood loss

Reversal: Animal Studies

Pragst, 2012• Study Design (n=28 rabbits)

• T=0 min, dabigatran iv• T=5 min, PCC infusion• T=10 min, kidney incision

Reversal: Animal StudiesPragst, 2012• Findings

• PCC reduced blood loss, bleeding time

• Dose dependent

Reversal: Animal StudiesPerzborn, 2013• Study Design – rats

• T=0 min, rivaroxaban iv• T=5 min, bleeding induced• T=6 min, reversal iv (PCC, aPCC, rFVIIa)

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Reversal: Animal StudiesPerzborn, 2013• Findings – rats

• n=7-12/group• All agents reduced bleeding time

• PCC• aPCC• rFVIIa

Reversal: Animal StudiesPerzborn, 2013• Study Design – baboons (n=7)

• T=0 min, rivaroxaban infusion• T=30 min, reversal agent• Experimental forearm incision • Bleeding time measured

Reversal: Animal StudiesPerzborn, 2013• Findings

• aPCC and rVIIa both reduced bleeding time• aPCC – from twice normal to normal• rFVIIa – from 2.5 normal to 1.7 normal

Reversal: Animal StudiesMartin, 2013• Study design

• T=0, simultaneous apixaban bolus and reversal agent bolus

• T=20 min hepatosplenic section • T=30 min, blood loss measured

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Reversal: Animal StudiesMartin, 2013• Findings

• rFVIIa partially corrected bleeding time• PCC, rFVIIa, fibrinogen did NOT reverse blood

Summary of Animal StudiesDabigatran

• PCC reversed dabigatran in 3/3 animal studies

Rivaroxaban and Apixaban• PCC, aPCC, rFVIIa reversed rivaroxaban

in 1/3 studies

Animal Studies: Limitations• Wide variability in study design

• Different doses • Different species• Different outcomes (coagulation assays,

bleeding time, blood loss)• Human clotting factors behave differently in

non-humans

Reversal: Specific AgentsHuman studiesAnimal studiesSpecific antidotes

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Reversal: Specific Antidotes• r-Antidote (PRT064445)• aDabi-Fab• PER977

Reversal: Specific Antidotesr-Antidote (PRT064445)

• Antidote for rivaroxaban• Recombinant protein• Binds Xa inhibitor site• Reduced blood loss in animal models• Not tested in humans

Lu, 2013

Reversal: Specific AntidotesaDabi-Fab

• Monoclonal antibody• Antidote for dabigatran• Reversed anticoagulant assays in rats

Schiele, 2013

Reversal: Specific Antidotes

PER977• Small synthetic molecule• Directly binds Xa and IIa• Reverses dabigatran, rivaroxaban, apixaban

Laulicht, 2012

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Summary Specific Antidotes• Three promising agents• None FDA-approved in humans yet


UCSF Guidelines UCSF GuidelinesCaveat:

No proven reversal agents or antidotes

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UCSF GuidelinesGeneral Principles

• Discontinue drug• Hemostasis• Hemodynamic support• Reverse other antithrombotic drugs

UCSF GuidelinesConsider • Hemodialysis (dabigatran only)• Activated charcoal

UCSF GuidelinesIf other measures fail

• Assess thrombotic risk• In past 6 wks

• MI• CVA, TIA• DVT/PE• Severe PVD

UCSF GuidelinesIf all measures fail

• aPCC (FEIBA®) to reverse dabigatran• PCC (Kcentra®) to reverse

rivaroxaban/apixaban

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FEIBA® and Kcentra® Cautions• Increase risk of thromboembolism• Reversal is OFF-LABEL

• Weigh risk/benefit• Blood products• Kcentra® contains heparin


Documents

Reversing the New Anticoagulants - UCSF CME11/6/2013 2 Roadmap for today • Characteristics of novel anticoagulants • Approach to the bleeding patient • Specific reversal agents